1. Field of the Invention
The invention relates to novel arginine and arginine-like compounds, compositions for treating ocular hypertension and methods for prevention of retinal degeneration employing the compositions. The invention also includes methods for stimulating nitric oxide (NO) production and activation of guanylate cyclase.
2. Description of Related Art
Ocular hypertension is a commonly encountered condition in the human eye and is particularly associated with glaucoma. Glaucoma and many other diseases and conditions such as diabetic retinopathy, sickle cell retinopathy, hypertensive and atherosclerotic vascular diseases, retinal vein occlusion and ischemic maculophaty may significantly effect retinal circulation and nutrient supply. Such impairment may lead to degeneration of the retina and optic nerve with ultimate loss of vision. Compounds that relieve ocular hypertension thus enhancing blood flow and nutrients supplied to the retina may slow or even prevent vision loss. However, many classes of compounds have systemic side effects that may be inappropriate for the condition treated, thus making it desirable to identify new agents with actions directed mainly to reduction of ocular hypertension.
To add to the problem, some drugs when given systemically or locally applied to the eye for reasons other than reduction of ocular hypertension may cause a decrease in ocular circulation generally as a side effect. Therefore, there are significant number of instances of decreased ocular flow resulting from unrelated disease conditions.
Treatment of open angle glaucoma is a typical case in point. Average incidences of open angle glaucoma in the general population at age 40 and older is relatively high, about 2-3% (Greco et al., 1979). Numerous compositions have been reported to be of value in treating such conditions as glaucoma by decreasing intraocular pressure (IOP). These compounds include alkaloids (EPA 257887), atrial natriuretic factor (ANF), peptides (EPO 291999A2), substituted 2-aminotetralins (U.S. Pat. No. 4,722,933), phenylimino-imidazoles (U.S. Pat. No. 4,515,800), betaxolol salts (U.S. Pat. No. 4,694,022), and vasodilators such as nitroglycerine (Nathanson, 1992). These compounds are representative of some of the agents that have been tested to reduce intraocular pressure. Interestingly, arginine and arginine derivatives have been suggested as prophylaxis or treatment of an animal for systemic hypotension induced by biological response modifiers such as tumor necrosis factor, interleukin-2 or endotoxin (Kilbourne, et al., WO 91/04024).
Unfortunately, while many of the compounds studied do indeed decrease IOP, there are other often undesirable physiologic effects. Some of these classes of ocular hypotensives may also have some degree of risk associated with use due mainly to toxicity, as well as mutagenic or immunosuppressive effects.
There is thus a continued need for improved pharmaceutical compounds for treatment of ocular hypertension and glaucoma that may be administered topically or otherwise that will act effectively and selectively in reducing intraocular pressure without other pharmacological action or untoward side effects. Particularly desirable agents are those effective in low dosages and which lack toxicity.